2,5-difluoro-4-methoxybenzaldehyde

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 250 mL round bottom flask was charged with 2,5-difluoro-4-methyoxybenzaldehyde (commercially available from Manchester Organics Ltd., UK) (18.45 g, 107.2 mmol), malonic acid (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (12.27 g, 117.9 mmol), and 10:1 EtOH/pyridine (27 mL). The mixture was stirred overnight at 70° C. under a reflux condenser and cooled to 0° C. for 2 hours. The precipitated solid was filtered, rinsed with ether, and dried in vacuo to afford H3.1 (16.96 g, 74% yield) as a white powder. cooled to 0° C. for 2 hours The precipitated solid was filtered rinsed with ether dried in vacuo to afford H3.1 (16.96 g, 74% yield) as a white powder

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 mL three RB flask fitted with magnetic stirrer was charged 1-Bromo-2,5-difluoro-4-methoxybenzene (1.0 g, 4.5 mmol) in 10 mL of THF, cooled −78° C. To the stirred solvent was added n-butyl lithium (3.09 mL, 1.6M solution, 4.95 mmol) drop wise and stirred at same temperature, was added DMF (0.375 g, 5.13 mmol), once the temperature to reached room temperature and stirred about 16 h. Then reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4. The removal of solvent under reduced pressure to obtain liquid product (0.77 g, yield: 100.0%). to reached room temperature stirred about 16 h Then reaction mixture was quenched with ice-cold water extracted with ethyl acetate The organic layer was washed with water dried over anhydrous Na2SO4 The removal of solvent under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 mL three RB flask fitted with magnetic stirrer was charged 1-Bromo-2,5-difluoro-4-methoxybenzene (1.0 g, 4.5 mmol) in 10 mL of THF, cooled −78° C. To the stirred solvent was added n-butyl lithium (3.09 mL, 1.6M solution, 4.95 mmol) drop wise and stirred at same temperature, was added DMF (0.375 g, 5.13 mmol), once the temperature to reached room temperature and stirred about 16 h. Then reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4. The removal of solvent under reduced pressure to obtain liquid product (0.77 g, yield: 100.0%). to reached room temperature stirred about 16 h Then reaction mixture was quenched with ice-cold water extracted with ethyl acetate The organic layer was washed with water dried over anhydrous Na2SO4 The removal of solvent under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 250 mL round bottom flask was charged with 2,5-difluoro-4-methyoxybenzaldehyde (commercially available from Manchester Organics Ltd., UK) (18.45 g, 107.2 mmol), malonic acid (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (12.27 g, 117.9 mmol), and 10:1 EtOH/pyridine (27 mL). The mixture was stirred overnight at 70° C. under a reflux condenser and cooled to 0° C. for 2 hours. The precipitated solid was filtered, rinsed with ether, and dried in vacuo to afford H3.1 (16.96 g, 74% yield) as a white powder. cooled to 0° C. for 2 hours The precipitated solid was filtered rinsed with ether dried in vacuo to afford H3.1 (16.96 g, 74% yield) as a white powder

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 250 mL round bottom flask was charged with 2,5-difluoro-4-methyoxybenzaldehyde (commercially available from Manchester Organics Ltd., UK) (18.45 g, 107.2 mmol), malonic acid (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (12.27 g, 117.9 mmol), and 10:1 EtOH/pyridine (27 mL). The mixture was stirred overnight at 70° C. under a reflux condenser and cooled to 0° C. for 2 hours. The precipitated solid was filtered, rinsed with ether, and dried in vacuo to afford H3.1 (16.96 g, 74% yield) as a white powder. cooled to 0° C. for 2 hours The precipitated solid was filtered rinsed with ether dried in vacuo to afford H3.1 (16.96 g, 74% yield) as a white powder

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 250 mL three RB flask fitted with magnetic stirrer was charged 1-Bromo-2,5-difluoro-4-methoxybenzene (1.0 g, 4.5 mmol) in 10 mL of THF, cooled −78° C. To the stirred solvent was added n-butyl lithium (3.09 mL, 1.6M solution, 4.95 mmol) drop wise and stirred at same temperature, was added DMF (0.375 g, 5.13 mmol), once the temperature to reached room temperature and stirred about 16 h. Then reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4. The removal of solvent under reduced pressure to obtain liquid product (0.77 g, yield: 100.0%). to reached room temperature stirred about 16 h Then reaction mixture was quenched with ice-cold water extracted with ethyl acetate The organic layer was washed with water dried over anhydrous Na2SO4 The removal of solvent under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 250 mL round bottom flask was charged with 2,5-difluoro-4-methyoxybenzaldehyde (commercially available from Manchester Organics Ltd., UK) (18.45 g, 107.2 mmol), malonic acid (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (12.27 g, 117.9 mmol), and 10:1 EtOH/pyridine (27 mL). The mixture was stirred overnight at 70° C. under a reflux condenser and cooled to 0° C. for 2 hours. The precipitated solid was filtered, rinsed with ether, and dried in vacuo to afford H3.1 (16.96 g, 74% yield) as a white powder. cooled to 0° C. for 2 hours The precipitated solid was filtered rinsed with ether dried in vacuo to afford H3.1 (16.96 g, 74% yield) as a white powder